title: PPARδ induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTOR activation.
abstract: The peroxisome proliferator-activated receptor-δ (PPARδ) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes are potential risk factors for the ability of PPARδ agonists to promote tumorigenesis in the mammary gland. In this study, we describe a new transgenic mouse model in which activation of PPARδ in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathologic changes that culminated in the appearance of estrogen receptor- and progesterone receptor-positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPARδ ligand GW501516 reduced tumor latency to 5 months. Histopathologic changes occurred concurrently with an increase in an inflammatory, invasive, metabolic, and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning 1 week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTOR signaling that were attenuated by treatment with the mTOR inhibitor everolimus. Our findings are the first to show a direct role of PPARδ in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease.
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Lombardi Comprehensive Cancer Center, Washington, DC 20007, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yuan
authors.forename: Jin
authors.initials: J
authors.lastname: Lu
authors.forename: Junfeng
authors.initials: J
authors.lastname: Xiao
authors.forename: Geeta
authors.initials: G
authors.lastname: Upadhyay
authors.forename: Rachel
authors.initials: R
authors.lastname: Umans
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.forename: Yuhzi
authors.initials: Y
authors.lastname: Yin
authors.forename: Michael E
authors.initials: ME
authors.lastname: Fant
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Robert I
authors.initials: RI
authors.lastname: Glazer
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D044584:Carcinoma, Ductal / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018734:Genes, erbB-2; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D058922:Inflammatory Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C425931:GW 501516; D047494:PPAR delta; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013844:Thiazoles; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases